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<p>Chronic sleep deprivation (CSD) can induce cognitive impairment, but its molecular mechanism remains unclear. In this study, initial m⁶A RNA sequencing of the hippocampal CA3 region in CSD rats, coupled with differential gene expression analysis of the total RNA fraction, revealed downregulation of <i>METTL3</i>, which was consistent with impaired performance in the Morris Water Maze (MWM) and confirmed by qRT-PCR and Western blot. Further investigation showed that, in HT-22 cells, <i>METTL3</i> knockdown exacerbated rapamycin-induced apoptosis. RNA sequencing of <i>METTL3</i>-knockdown cells identified gene modules and specific differentially expressed genes associated with <i>METTL3</i> loss. Differential expression analysis revealed that <i>CDKN1A</i> was significantly upregulated following <i>METTL3</i> knockdown. Methylated RNA immunoprecipitation followed by qPCR (MeRIP-qPCR) further showed that <i>METTL3</i> knockdown reduced the m⁶A methylation level of <i>CDKN1A</i> mRNA. In vivo, <i>METTL3</i> overexpression in CSD rats reduced <i>CDKN1A</i> levels, decreased neuronal apoptosis, improved spatial memory, and alleviated CA3 neuronal damage. In vitro, <i>METTL3</i> knockdown upregulated <i>CDKN1A</i> and promoted apoptosis in HT-22 cells, while <i>CDKN1A</i> knockdown reversed this effect. Collectively, our results demonstrate that <i>METTL3</i> downregulation promotes CSD-induced cognitive impairment by driving <i>CDKN1A</i>-dependent neuronal apoptosis, thereby identifying the <i>METTL3</i>/<i>CDKN1A</i> axis as a potential therapeutic target.</p>

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METTL3-mediated m6A modification regulates CDKN1A to attenuate chronic sleep deprivation-induced cognitive impairment and neuronal apoptosis in rats

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月9日

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  • Fei Xing,
  • Xiao-Shan Shi,
  • Han-Wen Gu,
  • Pan-Miao Liu,
  • Lei Lei,
  • Min Jia,
  • Xing-Ming Wang,
  • Mu-Huo Ji,
  • Jian-Jun Yang

摘要

Chronic sleep deprivation (CSD) can induce cognitive impairment, but its molecular mechanism remains unclear. In this study, initial m⁶A RNA sequencing of the hippocampal CA3 region in CSD rats, coupled with differential gene expression analysis of the total RNA fraction, revealed downregulation of METTL3, which was consistent with impaired performance in the Morris Water Maze (MWM) and confirmed by qRT-PCR and Western blot. Further investigation showed that, in HT-22 cells, METTL3 knockdown exacerbated rapamycin-induced apoptosis. RNA sequencing of METTL3-knockdown cells identified gene modules and specific differentially expressed genes associated with METTL3 loss. Differential expression analysis revealed that CDKN1A was significantly upregulated following METTL3 knockdown. Methylated RNA immunoprecipitation followed by qPCR (MeRIP-qPCR) further showed that METTL3 knockdown reduced the m⁶A methylation level of CDKN1A mRNA. In vivo, METTL3 overexpression in CSD rats reduced CDKN1A levels, decreased neuronal apoptosis, improved spatial memory, and alleviated CA3 neuronal damage. In vitro, METTL3 knockdown upregulated CDKN1A and promoted apoptosis in HT-22 cells, while CDKN1A knockdown reversed this effect. Collectively, our results demonstrate that METTL3 downregulation promotes CSD-induced cognitive impairment by driving CDKN1A-dependent neuronal apoptosis, thereby identifying the METTL3/CDKN1A axis as a potential therapeutic target.